1173C>T polymorphism in VKORC1 modulates the required warfarin dose
K Kosaki1, C Yamaghishi, R Sato
1Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Tokyo, Shinjuku-ku, 160-8582, Japan. kkosaki@sc.itc.keio.ac.jp
Pediatric Cardiology
|October 13, 2006
Summary
Genetic variations in VKORC1 influence warfarin dosage requirements in Japanese patients. Specific VKORC1 polymorphisms, linked to warfarin resistance, necessitate careful dosing adjustments for optimal patient outcomes.
Area of Science:
- Pharmacogenomics
- Genetics
- Cardiology
Background:
- Warfarin dosage response exhibits significant inter-individual variability.
- Genetic factors are strongly implicated in warfarin response variability.
- CYP2C9 *2 and *3 alleles are uncommon in the Japanese population.
Purpose of the Study:
- To investigate the impact of Vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphisms on warfarin response in a Japanese cohort.
- To correlate specific VKORC1 genetic variations with warfarin dosage needs.
Main Methods:
- Genotyping of VKORC1 polymorphisms (1173C>T and 3730G>A) in 31 pediatric patients on warfarin.
- Analysis of linkage disequilibrium between identified polymorphisms.
- Statistical adjustment for international normalized ratio (INR) to assess warfarin requirements.
Main Results:
- 84% of patients were T/T homozygotes and 16% were C/T heterozygotes for the VKORC1 1173C>T polymorphism.
- Complete linkage disequilibrium was observed between the 1173C>T and 3730G>A polymorphisms.
- VKORC1 C/T heterozygotes required significantly more warfarin than T/T homozygotes (p=0.003), adjusted for INR.
Conclusions:
- VKORC1 polymorphisms, specifically those in linkage disequilibrium with 1173C>T and 3730G>A, are associated with altered warfarin response in Japanese individuals.
- The functional impact may stem from a polymorphism near the studied sites, influencing warfarin metabolism.
- These findings highlight the importance of VKORC1 genotyping for personalized warfarin therapy.
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